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The Organic Chemistry of Enzyme-Catalyzed Reactions Revised Edition. Professor Richard B. Silverman Department of Chemistry Department of Biochemistry, Molecular Biology, and Cell Biology Northwestern University.
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Professor Richard B. Silverman
Department of Chemistry
Department of Biochemistry, Molecular Biology, and Cell Biology
The Organic Chemistry of Enzyme-Catalyzed ReactionsChapter 1Enzymes as Catalysts
Compounds having less bulky substituents often fail to be substrates
Some compounds with more bulky substituents bind more tightly
Some enzymes that catalyze reactions between two substrates do not bind one substrate until the other one is bound
When a substrate begins to bind to an enzyme, interactions induce a conformational change in the enzyme
Results in a change of the enzyme from a low catalytic form to a high catalytic form
Induced-fit hypothesis requires a flexible active site
Hypothesized that an enzyme is a flexible template that is most complementary to substrates at the transition state rather than at the ground state
Therefore, the substrate does not bind most effectively in the ES complex
As reaction proceeds, enzyme conforms better to the transition-state structure
Transition-state stabilization results in rate enhancement
Active site aligns the orbitals of substrates and catalytic groups on the enzyme optimally for conversion to the transition-state structure-- called orbital steering
Specificity of Binding
When k2 << k-1,
k2 called kcat (turnover number)
Ks called Km (Michaelis-Menten constant)
kcat represents the maximum number of substrate molecules converted to product molecules per active site per unit of time; called turnover number
Upper limit for is rate of diffusion (109 M-1s-1)
After bond breaking (or making) at transition state, interactions that match in the transition-state stabilizing complex are no longer present.
Therefore products are poorly bound, resulting in expulsion.
As bonds are broken/made, changes in electronic distribution can occur, generating a repulsive interaction, leading to expulsion of products
If Keq = 0.01, ∆Gº of -5.5 kcal/mol needed to shift Keq to 100
A type of dipole-dipole interaction between X-H and Y: (N, O)
Binding specificity of enantiomers
Steric hindrance to binding of enantiomers
Enzyme specificity for chemically identical protons. R and R on the enzyme are groups that interact specifically with R and R, respectively, on the substrate.
1010-1014 fold typically
Enzyme catalysis does not alter the equilibrium of a reversible reaction; it accelerates attainment of the equilibrium
Model Reaction for Covalent Catalysis
This is important for any reaction in which proton transfer occurs
Molecular dynamics simulations show interiors of these proteins have dielectric constants of about 2-3 (dielectric constant for benzene or dioxane)
Specific acid/base catalysis
General acid/base catalysis
Simultaneous acid/base catalysis is the reason for how enzymes are capable of deprotonating weak carbon acids
Simultaneous acid and base enzyme catalysis in the 1,4-elimination of -substituted (A) aldehydes, ketones, thioesters and (B) carboxylic acids
stronger acid needed
Needs acid or metal catalysis
The removal of water molecules at the active site
on substrate binding
Importance of ground state destabilization